Method of treating diseases

ABSTRACT

Methods of treating acromegaly in a subject are described herein. Exemplary methods include orally administering to the subject at least once daily at least one dosage form comprising octreotide, wherein the octreotide in each dosage form is 20 mg, and wherein the administering occurs at least 1 hour before a meal or at least 2 hours after a meal.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/233,749, filed on Dec. 27, 2018, which is a continuation of U.S.patent application Ser. No. 15/014,634, filed on Feb. 3, 2016, whichclaims priority under 35 U.S.C. 119(e) to U.S. Provisional PatentApplication Ser. No. 62/111,369, filed on Feb. 3, 2015 and U.S.Provisional Patent Application Ser. No. 62/136,012, filed Mar. 20, 2015,the contents of each of which is hereby incorporated herein by referencein its entirety.

FIELD OF THE TECHNOLOGY

The present invention relates to oral drug delivery of octreotide fortreating diseases.

BACKGROUND

Acromegaly, usually caused by a growth hormone-secreting pituitaryadenoma, is an inexorable chronic condition with significant morbidityand mortality (1). Hypersecretion of both GH and its target hormone,IGF-I, leads to acral disfigurement with bony overgrowth, hypertension,cardiac, cerebrovascular, and respiratory disease, arthritis and tissueswelling (2,3). In addition to pituitary tumor growth and/orpost-surgical recurrence, acromegaly co-morbidities occur especiallywith uncontrolled GH/IGF-I hypersecretion, and most are ameliorated byaggressively controlling GH/IGF-I levels (4-6). Acromegaly mortalitydeterminants include GH >2.5 ng/mL and elevated IGF-I, hypertension,cardiovascular and cerebrovascular disease, requirement forglucocorticoid replacement and prior pituitary radiation (4, 5, 7, 8).Effective surgical, radiation and medical strategies to improveco-morbidity and mortality require control of GH/IGF-I (9-11), (12,13).Treatments exhibit patient-specific efficacy and each manifests uniqueside effects (1,14-16).

Somatostatin inhibits pituitary GH secretion (17). Octreotide wasselected as a therapeutic because of its prolonged circulating half-lifecompared to native somatostatin (2 hours vs. 2 minutes)(18), as well asthe absence of acute rebound GH hypersecretion (19,20). Injections ofsomatostatin analogs acting as receptor ligands, also termedsomatostatin receptor ligands (SRL) include subcutaneous immediaterelease, intramuscular or deep subcutaneous depot preparations ofoctreotide and lanreotide (16,21-23). Both target mainly somatotrophSSTR2 receptors to suppress GH secretion and subsequent peripheral IGF-Iproduction (17,24,25). Currently available parenteral SRLs effectivelyachieve biochemical control and symptomatic improvement in acromegaly,yet these discomforting injections engender challenges to patients andhealth care providers. Although attempts to develop oral octreotide havebeen reported (26) (27), these formulations were not assessed further.

Idiopathic intracranial hypertension (IIH), sometimes called by theolder names benign intracranial hypertension (BIH) or pseudotumorcerebri (PTC), is a neurological disorder that is characterized byincreased intracranial pressure (pressure around the brain) in theabsence of a tumor or other diseases. It occurs most commonly in obeseyoung women but the cause is unknown. The main symptoms are headache,nausea, and vomiting, as well as pulsatile tinnitus (sounds perceived inthe ears, with the sound occurring in the same rhythm as the pulse),double vision and other visual symptoms. If the IIH is untreated, it maylead to papilledema (swelling of the optic disc in the eye) which canprogress to vision loss and blindness. Two reviews on the treatment ofIIH are Biousse J. Neurol Neurosurg Psychiatry 2012; 83:488-494 andLueck 2009 issue 4, The Cochrane Collaboration, published by John Wileyand sons. These reviews note that there is no general consensus on howIHH should be managed. Some forms of management are very expensive orhave significant complications or both. Several different treatmentshave been proposed ranging from relatively conservative measures such asdiuretic therapy and other drugs such as octreotide, acetrazolamide tomore invasive treatments such as optic nerve sheath fenestration,stenting of cerebral venous sinuses, or lumbo-peritoneal shunting;diagnostic lumbar puncture is a valuable intervention beyond itsdiagnostic importance, and weight management is critical whereappropriate.

The use of injected octreotide for this condition has been reported byPanagopoulos et al., Neurology, Neurophysiology and Neuroscience 2007:1;and by Deftereos et al., Cephalalgia, 2011, 31 (16), p. 1679). Upon useof daily injections of octreotide, headache and papilledema subsided andvisual disturbances improved in about 90% of patients treated. Treatmentcontinued for 6 months and then tapered off over another 2 months. LARdepot octreotide once monthly had a lower response rate.

The use of oral octreotide instead of the invasive procedures describedabove (e.g. daily injections, surgery) would be a great benefit topatients.

Vascular headaches, a group that includes migraines, are thought toinvolve abnormal function of the brain's blood vessels or vascularsystem. The most common type of vascular headache is migraine headachethat is usually characterized by severe pain on one or both sides of thehead, nausea and/or vomiting and disturbed vision and intolerance tolight. Other kinds of vascular headaches include cluster headaches andheadaches caused by a rise in blood pressure. In particular there is nosatisfactory prophylactic treatment for these conditions.

Injectable octreotide for cluster headaches and for migraines has beendescribed with varying results. (Matharu et al Ann Neurol 2004 October;56(4) 488-492; Levy et al Cephalgia 2005 January (1) 48-55. Miller et alAm J Emerg Med 2009 Feb. 27(2) 160-164. The use of oral octreotide isenvisaged for treatment and/or for prophylaxis of headaches, inparticular vascular headaches.

SUMMARY

The inventors of the present invention have discovered a method oftreating acromegaly and other diseases and conditions, includingidiopathic intracranial hypertension (IIH) and vascular headaches, in asubject, the method comprising orally administering to the subject atleast once daily at least one dosage form comprising an oily suspensioncomprising octreotide, wherein the octreotide in each dosage form isfrom about 5 mg to about 35 mg, and wherein the administering occurs atleast 1 hour before a meal or least 2 hours after a meal to therebytreat the subject.

Throughout this application, various publications, including UnitedStates patents, are referenced by author and year and patents andapplications by number. The disclosures of these publications andpatents and patent applications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this invention pertains.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D: Biochemical control. Boxplot of IGF-I (X ULN) (FIG. 1A,FIG. 1B) and mean integrated GH concentrations (ng/mL) (FIG. 1C, FIG.1D), by visit in the mITT (FIG. 1A, FIG. 1C) and Fixed Dose (FIG. 1B,FIG. 1D) cohorts. For the mITT population subjects terminating the trialearly during the dose escalation (n=41), appear at End of DoseEscalation and patients terminating early during the fixed dose (n=8)appear at End of Core. For the Fixed Dose population, patientsterminating the trial early during the fixed dose (n=8), and those notcontinuing into the extension (n=14), appear at End of Core. Endtreatment=end of 13 months. Dotted lines=GH and IGF1 screening andprimary end-points, respectively.

Mean=‘+’ symbol, Median=horizontal line within the box, 1stquartile=bottom of box, 3rd quartile=top of box Upper fence=3rdquartile+1.5 IQR, lower fence=1st quartile+1.5 IQR. IQR=interquartilerange. Whiskers are drawn to the most extreme points that lie betweenfences.

FIG. 2: Pharmacokinetic analysis in 46 subjects undergoing chronic OOCtreatment in their second visit of the fix-dose phase. PK was assessedafter the morning OOC dose for the 3 tested dosing regimens. A single 20mg capsule for 20 mg BID regimen (blue circles; n=21), two capsules of20 mg (40 mg total) of 40 mg+20 mg regimen (red triangles; n=11), and 2capsules of 20 mg (40 mg total) of 40 mg BID regimen (green rectangles;n=14). The arithmetic mean±standard error plasma octreotideconcentrations are presented on a logarithmic scale graph and a summaryof PK parameters for octreotide are presented as arithmetic mean±SD (n).

FIG. 3: Proportion of subjects with acromegaly signs and symptoms, byseverity in the fixed dose population from screening to end of treatment(including extension). Screening, baseline and TA1 (first OOCadministration) depict symptoms on parenteral SRL injections. End ofcore and end of treatment depict symptoms while on OOC. For thisanalysis the last observed value on OOC was carried forward to end oftreatment.

FIG. 4: A flowchart of the study described in the Examples.

DETAILED DESCRIPTION OF THE INVENTION

Treatment of Acromegaly

Acromegaly is caused by a benign (non-cancerous) tumor (an adenoma)within the pituitary gland that secretes excess growth hormone (GH),leading to elevated levels of insulin-like growth factor-1 (IGF-1). Thiscombined effect of elevated GH and IGF-1 levels causes the enlargementof body parts, including the hands, feet and facial features, along withserious morbidities such as cardiovascular, metabolic and respiratorydiseases. If exposed to long-term elevated levels of GH and IGF-1,acromegaly patients face a two- to three-fold increased risk of death.

The current treatment of acromegaly is summarized by Giustina et al2014(Ref 13) which is hereby incorporated by reference. Biochemicalcontrol of the disease, as measured by both GH and IGF-1 levels, is theprimary goal of treatment. Other disease management objectives includetumor shrinkage and improvement in clinical signs and symptoms. Thus themain goals of treatment are to control GH and IGF-1 levels and tocontrol acromegaly symptoms.

Various forms of pharmaceutical therapy are used in the art fortreatment of acromegaly: most are receptor-based, directed at thepituitary adenoma (the somatostatin receptor ligands—SRLs—octreotide,lanreotide and pasireotide which are all given by injection) and thedopamine agonist cabergoline given orally; and one is directed atdecreasing and/or blocking GH effects in the periphery viz., the GHreceptor antagonist pegvisomant given by injection. SRLs may be given inslow release formulation or in an immediate release formulation.

Surgery is the primary treatment option if the tumor is resectable. SRLs(injectable octreotide or injectable lanreotide) are the primaryfirst-line treatment after surgery and are the primary treatment optionif surgery is not appropriate. Some physicians prescribe dopamineagonists as the primary first-line treatment after surgery. SRLs anddopamine agonists and pegvisomant may also be given before surgery orinstead of surgery.

The octreotide capsule described herein is an oral product indicated forlong-term maintenance therapy in acromegaly patients; in certainembodiments the patients are those in whom prior treatment withsomatostatin analogs (by injection) has been shown to be effective andtolerated. The goal of treatment in acromegaly is to control GH andIGF-1 levels and to lower the GH and IGF-1 levels to as close to normalas possible.

The oral octreotide capsule should preferably be administered with aglass of water on an empty stomach (i.e., at least 1 hour prior to ameal or at least 2 hours after a meal).

Patients currently receiving somatostatin analog therapy by injectioncan be switched to octreotide capsules with an initial dose of 20 mg BIDgiven orally. Blood levels of IGF-1 and clinical symptoms should bemonitored. If IGF-1 is normal and clinical symptoms are controlled orresponse level (biochemical and symptomatic response) is maintained,maintain oral octreotide capsule dosage at 20 mg BID (ie 40 mg daily).Dosage may be adjusted to 60 mg daily (40 mg morning+20 mg evening) ifIGF-1 levels are increased, as determined by the treating physician, orin case of symptomatic exacerbation. Monitoring is continued, whileapplying the above algorithm for maintaining or increasing the dose upto 40 mg BID is 80 mg daily. The administering throughout occurs atleast 2 hours after a meal, or at least 1 hour before a meal.

In another embodiment of the invention, if a capsule containing about 30mg octreotide is administered, then the above algorithm is used toadjust the dose from 60 mg daily to 90 mg daily and a maximum of 120 mgdaily; wherein the administering occurs at least 2 hours after a meal,or at least 1 hour before a meal. In another embodiment, if a capsulecontaining about 30 mg octreotide is administered, then the abovealgorithm is used to adjust the dose from 30 mg daily (only one capsuletaken) to 60 mg daily to 90 mg daily and a maximum of 120 mg daily;wherein the administering occurs at least 2 hours after a meal, or atleast 1 hour before a meal.

In a further embodiment of the invention, if a capsule containing lessthan 20 mg octreotide is administered e.g. 10 mg, then the abovealgorithm is adjusted concomitantly. For example in an embodiment of theinvention, if a capsule containing about 10 mg octreotide isadministered, then the above algorithm is used to adjust the dose from20 mg daily to 30 mg daily and a maximum of 60 mg daily as needed;wherein the administering occurs at least 2 hours after a meal, or atleast 1 hour before a meal.

The invention may be used in the treatment of naïve patients or patientsalready treated with parenteral injections.

Patients who are not adequately controlled following dose titration canreturn to therapy by injections at any time. Proton pump inhibitors(PPIs), H2-receptor antagonists, and antacids may lead to a higherdosing requirement of oral octreotide to achieve therapeutic levels.

One embodiment of the invention is a method of treating acromegaly in asubject, the method comprising orally administering to the subject atleast once daily at least one dosage form comprising an oily suspensioncomprising octreotide, wherein the octreotide in each dosage form isfrom about 5 mg to about 35 mg (e.g. 5, 10, 15, 20, 25, 30 or 35 mg),and wherein the administering occurs at least 1 hour before a meal or atleast 2 hours after a meal, to thereby treat the subject. Anotherembodiment of the invention is a method of treating acromegaly in asubject, the method comprising orally administering to the subject atleast once daily at least one dosage form comprising an oily suspensioncomprising octreotide, wherein the octreotide in each dosage form isfrom about 18 mg to about 22 mg, and wherein the administering occurs atleast 1 hour before a meal or at least 2 hours after a meal to therebytreat the subject.

A dosage form is essentially a pharmaceutical product in the form inwhich it is marketed for use, typically involving a mixture of activedrug components and nondrug components (excipients), along with othernon-reusable material that may not be considered either ingredient orpackaging (such as a capsule shell, for example).

The oily suspension as used herein comprises an admixture of ahydrophobic medium (lipophilic fraction) and a solid form (hydrophilicfraction) wherein the solid form comprises a octreotide and at least onesalt of a medium chain fatty acid, and wherein the medium chain fattyacid salt is present in the composition at an amount of 10% or more byweight such as 11%-15%, or 11%, 12%, 13%, 14%, 15% or more by weight.

Oral formulations of octreotide, comprising the oily suspension, havebeen described and claimed, for example in co-assigned U.S. Pat. No.8,329,198 which is hereby incorporated by reference; see for exampleclaims 1-26.

In a particular embodiment of the method of the invention the oilysuspension is formulated into a capsule, which may be entericallycoated. In another embodiment of the method of the invention the capsuleconsists of an oily suspension. In another embodiment of the method ofthe invention the subject is dosed every 8-16 hours (e.g., every 12hours). In another embodiment of the method of the invention oneadministration takes place at least 6, 8, 10 or 12 hours before a secondadministration. In a preferred embodiment the subject is a human.

For clarity, the twice daily administration comprises a firstadministration and a second administration. In a further embodiment afirst administration includes one or two dosage forms and a secondadministration includes one or two dosage forms, and more particularlythe first administration includes one dosage form and the secondadministration includes one dosage form, or the first administrationincludes two dosage forms and the second administration includes onedosage form, or the first administration includes two dosage forms andthe second administration includes two dosage forms. In embodiments ofthe invention the first administration is in the morning (normally 5 amto noon) and the second administration is in the evening (normally 5 pmto midnight). All the administering occurs at least 1 hour before a mealor at least 2 hours after a meal.

Particular embodiments of the invention are as follows: one dosage formis administered twice daily; two dosage forms are administered once aday and one dosage form is administered once a day; and two dosage formsare administered twice daily. Other embodiments of the invention are asfollows: one dosage form is administered once a day; two dosage formsare administered once a day; three or more dosage forms are administeredonce a day; and two or more dosage forms (e.g. three dosage forms) areadministered twice a day. All the administering occurs at least 1 hourbefore a meal or at least 2 hours after a meal.

In some embodiments of the invention, the administration may beself-administration; in other embodiments of the invention or acaregiver or health professional may administer the dosage form.

In certain embodiments of the invention each dosage form comprises fromabout 19 to about 21 mg of octreotide and in a particular embodiment ofthe invention each dosage form comprises 20 mg of octreotide which isabout 3% w/w octreotide or 3.3% w/w octreotide. In certain embodimentsof the invention the total amount of octreotide administered per day isfrom about 36 to about 44 mg (e.g., from about 38 to about 42 mg, or 40mg). In certain embodiments of the invention the total amount ofoctreotide administered per day is from about 54 to about 66 mg (e.g.,from about 57 to about 63 mg, or 60 mg). In certain embodiments of theinvention the total amount of octreotide administered per day is fromabout 72 to about 88 mg (e.g., from about 76 to about 84 mg, or 80 mg).In certain embodiments of the invention the total amount of octreotideadministered per day is from about 90 to about 110 mg (e.g., from about95 to about 105 mg, or 100 mg). All the administering occurs at least 1hour before a meal or at least 2 hours after a meal.

In certain embodiments of the invention each dosage form comprises fromabout 27 to about 33 mg of octreotide and in a particular embodiment ofthe invention each dosage form comprises 30 mg of octreotide which isabout 5% w/w octreotide or 4.96% w/w octreotide. This may beadministered as one, two, three or four capsules per day, whereinadministering occurs at least 1 hour before a meal or at least 2 hoursafter a meal.

In another embodiments of the invention each dosage form comprises lessthan 20 mg octreotide and in a particular embodiment of the inventioneach dosage form comprises about 10 mg. This may be administered as one,two, three or four capsules per day, wherein administering occurs atleast 1 hour before a meal or at least 2 hours after a meal.

In further embodiments, the method of the invention occurs over aduration of at least 7 months, occurs over a duration of at least 13months and over a duration of greater than 13 months. In a particularembodiment the method of treatment is for long-term maintenance therapy.Long-term maintenance therapy in a subject suffering from acromegalycontinues as long as the subject is suffering from acromegaly and theIGF-1 levels are maintained at equal or less than 1.3 times the upperlimit of the age-adjusted normal range (ULN). Thus the duration may beunlimited. In particular embodiments the long-term maintenance therapymay be for at least one, two, three, four or five years. In a particularembodiment upon administration of octreotide, an in vivo amount ofgrowth hormone integrated over 2 hours is obtained which is equal orless than 2.5 ng/mL or equal or less than 1.0 ng/mL.

In further embodiments, upon administration of octreotide, an in vivoconcentration of IGF-I is obtained of equal or less than 1.3 times theupper limit of the age-adjusted normal range (ULN), or equal or lessthan 1.0 or 1.1 or 1.2 or 1.4 or 1.5 or 1.6 times the upper limit of theage-adjusted normal range (ULN).

In certain embodiments, an in vivo mean peak plasma concentration uponadministration of octreotide of about 3.5+/−0.5 ng/mL is achieved. Incertain embodiments an in vivo mean area under the curve uponadministration of octreotide is about 15+/−4 h×ng/mL is obtained.

In particular embodiments of the method of the invention the subject hashad prior treatment for acromegaly, and the prior treatment foracromegaly was surgical and/or medicinal; in certain embodiments themedicinal treatment was a somatostatin analog (=somatostatin receptorligand) e.g. injectable octreotide or injectable lanreotide orinjectable pasireotide and/or a dopamine agonist e.g. cabergoline and/ora GH receptor antagonist e.g. pegvisomant.

In particular embodiments the prior treatment of the subject with asomatostatin analog has been shown to be effective and tolerated.

In particular embodiments the prior treatment of the subject produced anIGF-1 level in the subject of equal or less than 1.3 times upper limitof normal (ULN), and/or prior treatment of the subject produced 2-hourintegrated growth hormone (GH) of less than 2.5 ng/mL or less than 1.0ng/mL

Preferably the oral octreotide capsule should be administered on anempty stomach (i.e., at least 1 hour prior to a meal or at least 2 hoursafter a meal. In particular embodiments of all inventions describesherein, a meal comprises 100-1000 calories, or 300-600 calories whichmay be a high-fat meal or a high calorie meal and may comprisecarbohydrates and/or fat and or protein e.g. 100, 200, 300, 400 caloriesor 500-1000 calories or 700-800 calories.

The invention also contemplates titrating a patient suffering fromacromegaly to determine the effective dose of octreotide. Such anembodiment of the invention relates to a method of titrating a patienthaving acromegaly, the method comprising orally administering to thesubject at least once daily (e.g. twice daily) at least one dosage formcomprising an oily suspension comprising octreotide, wherein theoctreotide in each dosage form is from about 18 mg to about 22 mg,wherein the total amount of octreotide administered per day is fromabout 36 to about 44 mg; and subsequent to the administration,evaluating an IGF-1 level (and/or a GH level) in a subject and comparingthe level to a reference standard; wherein if the IGF-1 level (and/orthe GH level) is above the reference standard, increasing the totalamount of octreotide administered per day to from about 54 to about 66mg; wherein the administering occurs at least 2 hours after a meal, orat least 1 hour before a meal.

Another such embodiment of the invention relates to a method oftitrating a patient having acromegaly, the method comprising orallyadministering to the subject at least once daily (e.g. twice daily) atleast one dosage form comprising an oily suspension comprisingoctreotide, wherein the octreotide in each dosage form is from about 18mg to about 22 mg, wherein the total amount of octreotide administeredper day is from about 54 to about 66 mg; and subsequent to theadministration, evaluating an IGF-1 level (and/or a GH level) in asubject and comparing the level to a reference standard; wherein if theIGF-1 level (and/or the GH level) is above the reference standard,increasing the total amount of octreotide administered per day to fromabout 72 to about 88 mg; wherein the administering occurs at least 2hours after a meal or at least 1 hour before a meal.

In one embodiment of the invention, if a capsule containing about 30 mgoctreotide is administered, then the above algorithm is used to adjustthe dose from 60 mg daily to 90 mg daily and a maximum of 120 mg daily;wherein the administering occurs at least 2 hours after a meal, or atleast 1 hour before a meal. In another embodiment, if a capsulecontaining about 30 mg octreotide is administered, then the abovealgorithm is used to adjust the dose from 30 mg daily (only one capsuletaken) to 60 mg daily (two capsules) to 90 mg daily (three capsules) anda maximum of 120 mg daily (four capsules); wherein the administeringoccurs at least 2 hours after a meal, or at least 1 hour before a meal.

In a further embodiment of the invention, if a capsule containing lessthan 20 mg octreotide is administered e.g. 10 mg, then the abovealgorithm is adjusted concomitantly.

In further embodiments of the titrating invention the oily suspension isformulated into a capsule; the capsule is enterically coated; the oraladministration is twice daily comprising a first and secondadministration; the subject is dosed every 8-16 hours (e.g., every 12hours); one administration takes place at least 6, 8, 10 or 12 hoursbefore a second administration; and the subject is a human. In a furtherembodiment of the titrating invention the first administration prior toevaluation includes one or two dosage forms and the secondadministration includes one or two dosage forms. In a further embodimentof the titrating invention, the first daily administration prior toevaluation includes one dosage form and the second daily administrationprior to evaluation includes one dosage form. In a further embodiment ofthe titrating invention the first daily administration prior toevaluation includes two dosage forms and the second daily administrationprior to evaluation includes one dosage form. In a further embodiment ofthe titrating invention the first daily administration after evaluationincludes two dosage forms and the second daily administration afterevaluation includes two dosage forms. In a further embodiment of theinvention one dosage form is administered once a day and two dosageforms are administered once a day, prior to evaluation. In a furtherembodiment of the invention two dosage forms are administered twicedaily after evaluation. Administering occurs at least 2 hours after ameal, or at least 1 hour before a meal.

In a further embodiment of the invention each dosage form comprises fromabout 19 to about 21 mg of octreotide, more particularly 20 mg ofoctreotide which is about 3% w/w octreotide. In a further embodiment ofthe invention the total amount of octreotide administered per day priorto evaluation is from about 36 to about 44 mg (e.g., from about 38 toabout 42 mg, or 40 mg). In a further embodiment of the invention thetotal amount of octreotide administered per day prior to evaluation isfrom about 54 to about 66 mg (e.g., from about 57 to about 63 mg, or 60mg).

In a further embodiment of the invention the total amount of octreotideadministered per day subsequent to evaluation is from about 54 to about66 mg (e.g., from about 57 to about 63 mg, or 60 mg). In a furtherembodiment of the invention the total amount of octreotide administeredper day subsequent to evaluation is from about 72 to about 88 mg (e.g.,from about 76 to about 84 mg, or 80 mg). In a further embodiment of theinvention the evaluation takes place at least two months from start oftherapy (i.e. from start of administration of the dosage forms), 2-5months from start of therapy or after 5 months from start of therapy(e.g. after 5, 6, 7 or 8 months or more from start of therapy).

In a specific embodiment of the invention the blood levels of IGF-1 andclinical symptoms are monitored when oral octreotide capsule dosage at40 mg (20 mg BID), and if IGF-1 is normal and clinical symptoms arecontrolled or response level (biochemical and symptomatic response) ismaintained, then oral octreotide capsule dosage is continued at 40 mg(20 mg BID). In a further specific embodiment of the invention the bloodlevels of IGF-1 and clinical symptoms are further monitored when oraloctreotide capsule dosage is at 40 mg, and if IGF-1 is not normal andclinical symptoms are not controlled or response level (biochemical andsymptomatic response) is not maintained, then oral octreotide capsuledosage is increased to 60 mg daily (40 mg morning+20 mg evening). In afurther specific embodiment of the invention the blood levels of IGF-1and clinical symptoms are further monitored when oral octreotide capsuledosage is at 60 mg, and if IGF-1 is normal and clinical symptoms arecontrolled or response level (biochemical and symptomatic response) ismaintained, then oral octreotide capsule dosage is continued at 60 mgdaily. In a further specific embodiment of the invention the bloodlevels of IGF-1 and clinical symptoms are further monitored when oraloctreotide capsule dosage is at 60 mg, and if IGF-1 is not normal andclinical symptoms are not controlled or response level (biochemical andsymptomatic response) is not maintained, then oral octreotide capsuledosage is increased to 80 mg (40 mg morning+40 mg evening)

In a further embodiment of the invention the reference standard is an invivo amount of growth hormone integrated over 2 hours is obtained whichis equal or less than 2.5 ng/mL (for example equal or less than 1.0ng/mL). In a further embodiment of the invention the reference standardis an in vivo concentration of IGF-I is obtained of equal or less than1.3 times the upper limit of the age-adjusted normal range (ULN). In afurther embodiment of the invention an in vivo mean peak plasmaconcentration upon administration of octreotide after evaluation isabout 3.5+/−0.5 ng/mL. In a further embodiment of the invention an invivo mean area under the curve upon administration of octreotide afterevaluation is about 15+/−4 h×ng/mL. In a further embodiment of thetitrating invention the subject has had prior treatment for acromegalywhich was surgical and/or pharmaceutical e.g. the pharmaceuticaltreatment was a somatostatin receptor ligand e.g. octreotide orlanreotide and was administered by injection. In a further embodiment ofthe titrating invention prior treatment of the subject with asomatostatin analog has been shown to be effective and tolerated. In afurther embodiment of the invention the prior pharmaceutical treatmentwas pegvisomant or a dopamine agonist e.g. cabergoline.

In a further embodiment of the invention, prior treatment of the subjectproduced an IGF-1 level in the subject of equal or less than 1.0 to 1.5times upper limit of normal (ULN) e.g. equal or less than 1.3 timesupper limit of normal (ULN). In a further embodiment of the inventionprior treatment of the subject produced 2-hour integrated growth hormone(GH) of less than 2.5 ng/mL e.g. less than 1.0 ng/mL.

A further embodiment of the invention is a method of predictingsubsequent response to oral octreotide capsules in a patient receivinginjectable treatment. Thus an embodiment of the invention is a method ofpredicting subsequent response to oral octreotide capsules comprisingthe oily suspension in a patient suffering from acromegaly, the methodcomprising measuring the degree of baseline control on injectable SRLs;and thereby determining if the patient is likely to respond to the oraloctreotide capsules. In an embodiment of the invention the desiredbaseline control is IGF-I ≤1ULN and GH <2.5 ng/mL when the patient ismaintained on low to mid doses of injectable SRLs (octreotide <30 mg orlanreotide <120 mg).

Treatment of Idiopathic Intracranial Hypertension (IIH)

Another embodiment of the invention is a method of treating idiopathicintracranial hypertension (IIH) in a subject, the method comprisingorally administering to the subject at least once daily at least onedosage form comprising an oily suspension comprising octreotide, whereinthe octreotide in each dosage form is from about 5 mg to about 35 mg(e.g. 5, 10, 15, 20, 25, 30 or 35 mg), and wherein the administeringoccurs at least 1 hour before a meal or at least 2 hours after a meal,to thereby treat the subject. In a particular embodiment the octreotidein each dosage form is from about 18 mg to about 22 mg. In anotherembodiment the octreotide in each dosage form is from about 27 mg toabout 33 mg e.g. about 30 mg.

The oily suspension as used herein comprises an admixture of ahydrophobic medium (lipophilic fraction) and a solid form (hydrophilicfraction) wherein the solid form comprises a octreotide and at least onesalt of a medium chain fatty acid, and wherein the medium chain fattyacid salt is present in the composition at an amount of 10% or more byweight such as 11%-15%, or 11%, 12%, 13%, 14%, 15% or more by weight.The oily suspension of the invention is as described herein. In aparticular embodiment of the method of the invention the oily suspensionis formulated into a capsule, which may be enterically coated. Inanother embodiment of the method of the invention the capsule consistsof an oily suspension. In another embodiment of the method of theinvention the subject is dosed every 8-16 hours (e.g., every 12 hours).In another embodiment of the method of the invention one administrationtakes place at least 6, 8, 10 or 12 hours before a secondadministration. In a preferred embodiment the subject is a human.

For clarity, the twice daily administration comprises a firstadministration and a second administration. In a further embodiment afirst administration includes one or two dosage forms and a secondadministration includes one or two dosage forms, and more particularlythe first administration includes one dosage form and the secondadministration includes one dosage form or the first administrationincludes two dosage forms and the second administration includes onedosage form or the first administration includes two dosage forms andthe second administration includes two dosage forms. In embodiments ofthe invention the first administration is in the morning (normally 5 amto noon) and the second administration is in the evening (normally 5 pmto midnight).

Particular embodiments of the invention are as follows: one dosage formis administered twice daily; two dosage forms are administered once aday and one dosage form is administered once a day; and two dosage formsare administered twice daily. Other embodiments of the invention are asfollows: one dosage form is administered once a day; two dosage formsare administered once a day; three or more dosage forms are administeredonce a day; and two or more dosage forms (e.g. three dosage forms) areadministered twice a day.

In some embodiments of the invention, the administration may beself-administration; in other embodiments of the invention or acaregiver or health professional may administer the dosage form.

In certain embodiments of the invention each dosage form comprises fromabout 19 to about 21 mg of octreotide and in a particular embodiment ofthe invention each dosage form comprises 20 mg of octreotide which isabout 3% w/w octreotide or 3.3% w/w octreotide. In certain embodimentsof the invention the total amount of octreotide administered per day isfrom about 36 to about 44 mg (e.g., from about 38 to about 42 mg, or 40mg). In certain embodiments of the invention the total amount ofoctreotide administered per day is from about 54 to about 66 mg (e.g.,from about 57 to about 63 mg, or 60 mg). In certain embodiments of theinvention the total amount of octreotide administered per day is fromabout 72 to about 88 mg (e.g., from about 76 to about 84 mg, or 80 mg).In certain embodiments of the invention each dosage form comprises fromabout 5 to about 35 mg of octreotide and in a particular embodiment ofthe invention each dosage form comprises about 5 or 10 or 15 or 20 or 25or 30 or 35 mg of octreotide.

In further embodiments of the invention the method occurs over aduration of at least 7 months or more. In further embodiments of theinvention the method can be tapered off after a few months e.g. over 2months or more. In further embodiments of the invention the method canbe tapered off after about 2, 3, 4, 5, 6, 7, 8, 9, or 10 months or more.

In further embodiments of the invention the capsule comprises 20 mgoctreotide which is about 3% w/w octreotide. In further embodiments ofthe invention the capsule comprises about 10 mg octreotide or about 30mg octreotide.

In further embodiments of the invention the oily suspension comprises anadmixture of a hydrophobic medium (lipophilic fraction) and a solid form(hydrophilic fraction) wherein the solid form comprises a octreotide andat least one salt of a medium chain fatty acid, and wherein the mediumchain fatty acid salt is present in the composition at an amount of 10%or more by weight (e.g. at an amount of 11%-16% or more such as 11%,12%, 13%, 14%, 15%, 16% by weight).

In particular embodiments of the invention upon administration ofoctreotide, headache is relieved. In particular embodiments of theinvention upon administration of octreotide, visual disturbances arereduced. In particular embodiments of the invention upon administrationof octreotide, papilledema subside. In particular embodiments of theinvention upon administration of octreotide, the CSF opening pressure isreduced e.g. to to 8-23 cm H₂O preferably 10-18 cm H₂O.

In another embodiment another SRL (e.g., lanreotide) may be used orallyto treat IIH. Thus an embodiment of the invention is a method oftreating idiopathic intracranial hypertension (IIH) in a subject, themethod comprising orally administering to the subject at least oncedaily at least one dosage form containing lanreotide to thereby treatthe subject. In a specific embodiment the administering occurs at least1 hour before a meal or at least 2 hours after a meal.

The invention also contemplates titrating a patient suffering from IIHto determine the effective dose of octreotide.

This embodiment comprises titrating a patient having idiopathicintracranial hypertension (IIH), the method comprising orallyadministering to the subject at least once daily at least one dosageform comprising an oily suspension comprising octreotide, wherein theoctreotide in each dosage form is from about 18 mg to about 22 mg,wherein the total amount of octreotide administered per day is fromabout 36 to about 44 mg; and subsequent to the administration,evaluating an IIH symptom in a subject and comparing the level to areference standard; wherein if the IIH symptom is above the referencestandard, increasing the total amount of octreotide administered per dayto from about 54 to about 66 mg; wherein the administering occurs atleast 1 hour before a meal or at least 2 hours after a meal.

In one embodiment of the invention, if a capsule containing about 30 mgoctreotide is administered, then the above algorithm is used to adjustthe dose from 60 mg daily to 90 mg daily and a maximum of 120 mg daily;wherein the administering occurs at least 2 hours after a meal, or atleast 1 hour before a meal. In another embodiment, if a capsulecontaining about 30 mg octreotide is administered, then the abovealgorithm is used to adjust the dose from 30 mg daily (only one capsuletaken) to 60 mg daily to 90 mg daily and a maximum of 120 mg daily;wherein the administering occurs at least 2 hours after a meal, or atleast 1 hour before a meal.

In a further embodiment of the invention, if a capsule containing lessthan 20 mg octreotide is administered e.g. 10 mg, then the abovealgorithm is adjusted concomitantly.

This embodiment also comprises a method of titrating a patient havingidiopathic intracranial hypertension (IIH), the method comprising orallyadministering to the subject at least once daily at least one dosageform comprising an oily suspension comprising octreotide, wherein theoctreotide in each dosage form is from about 18 mg to about 22 mg,wherein the total amount of octreotide administered per day is fromabout 54 to about 66 mg; and subsequent to the administration,evaluating an IIH symptom in a subject and comparing the level to anormal reference standard; wherein if symptom is above the referencestandard, increasing the total amount of octreotide administered per dayto from about 72 to about 88 mg; wherein the administering occurs atleast 2 hours after a meal or at least 1 hour before a meal.

In further embodiments of the titrating invention the oily suspension isformulated into a capsule; the capsule is enterically coated; the oraladministration is twice daily comprising a first and secondadministration; the subject is dosed every 8-16 hours (e.g., every 12hours); one administration takes place at least 6, 8, 10 or 12 hoursbefore a second administration; and the subject is a human. In a furtherembodiment of the titrating invention the first administration prior toevaluation includes one or two dosage forms and the secondadministration includes one or two dosage forms. In a further embodimentof the titrating invention, the first daily administration prior toevaluation includes one dosage form and the second daily administrationprior to evaluation includes one dosage form. In a further embodiment ofthe titrating invention the first daily administration prior toevaluation includes two dosage forms and the second daily administrationprior to evaluation includes one dosage form. In a further embodiment ofthe titrating invention the first daily administration after evaluationincludes two dosage forms and the second daily administration afterevaluation includes two dosage forms. In a further embodiment of theinvention one dosage form is administered once a day and two dosageforms are administered once a day, prior to evaluation. In a furtherembodiment of the invention two dosage forms are administered twicedaily after evaluation.

In a further embodiment of the invention each dosage form comprises fromabout 19 to about 21 mg of octreotide, more particularly 20 mg ofoctreotide which is about 3% w/w octreotide. In a further embodiment ofthe invention the total amount of octreotide administered per day priorto evaluation is from about 36 to about 44 mg (e.g., from about 38 toabout 42 mg, or 40 mg). In a further embodiment of the invention thetotal amount of octreotide administered per day prior to evaluation isfrom about 54 to about 66 mg (e.g., from about 57 to about 63 mg, or 60mg).

In a further embodiment of the invention the total amount of octreotideadministered per day subsequent to evaluation is from about 54 to about66 mg (e.g., from about 57 to about 63 mg, or 60 mg). In a furtherembodiment of the invention the total amount of octreotide administeredper day subsequent to evaluation is from about 72 to about 88 mg (e.g.,from about 76 to about 84 mg, or 80 mg). In a further embodiment of theinvention the evaluation takes place about one week or one month fromstart of therapy (i.e. from start of administration of the dosageforms), 2-5 months from start of therapy or after 5 months from start oftherapy (e.g. after 5, 6, 7 or 8 months or more from start of therapy).

In a further embodiment of the titrating invention, the oily suspensioncomprises an admixture of a hydrophobic medium (lipophilic fraction) anda solid form (hydrophilic fraction) wherein the solid form comprises aoctreotide and at least one salt of a medium chain fatty acid, andwherein the medium chain fatty acid salt is present in the compositionat an amount of 10% or more by weight (e.g. at an amount of 11%-16% ormore such as 11%, 12%, 15%, 16% by weight). In a particular embodimentthe capsule comprises 20 mg octreotide which is about 3% w/w octreotide.In another particular embodiment the capsule comprises about 10 mgoctreotide or about 30 mg octreotide.

In a further embodiment of the titrating invention the IIH symptom isone or more of headache, papilledema and visual disturbance. In afurther embodiment of the titrating invention the reference standard isthe normal for a healthy person not suffering from IIH e.g. no headache,no papilledema and no visual disturbance.

Treatment of Vascular Headaches

A further embodiment of the invention is a method of treating orprophylaxis of headaches in particular vascular headaches, which arethought to involve abnormal function of the brain's blood vessels orvascular system. The most common type of vascular headache is migraineheadache. Other kinds of vascular headaches include cluster headachesand headaches caused by a rise in blood pressure.

Migraines typically present with self-limited, recurrent severe headacheassociated with autonomic symptoms.

Cluster headache is a neurological disorder characterized by recurrent,severe headaches on one side of the head, typically around the eye.There are often accompanying autonomic symptoms during the headache suchas eye watering, nasal congestion and swelling around the eye, typicallyconfined to the side of the head with the pain.

The use of oral octreotide is envisaged to treat headaches in particularvascular headaches including migraines and cluster headaches. Thus anembodiment of the invention is a method of treating headaches inparticular vascular headaches including migraines and cluster headachesin a subject, the method comprising orally administering to the subjectat least once daily at least one dosage form containing octreotide tothereby treat the subject. In a specific embodiment, the administeringoccurs at least 1 hour before a meal or at least 2 hours after a meal.The treatment may comprise aborting a headache or prophylactic treatmentwherein oral octreotide is taken on an ongoing prophylactic basis.

In another embodiment another SRL (e.g., lanreotide) may be used orallyto treat headaches in particular vascular headaches including migrainesand cluster headaches. Thus an embodiment of the invention is a methodof treating headaches in particular vascular headaches includingmigraines and cluster headaches in a subject, the method comprisingorally administering to the subject at least once daily at least onedosage form containing lanreotide to thereby treat the subject. In aspecific embodiment the administering occurs at least 1 hour before ameal or at least 2 hours after a meal. The treatment may compriseaborting a headache or prophylactic treatment wherein oral lanreotide istaken on an ongoing prophylactic basis.

A particular embodiment of the invention is a method of prophylacticallytreating or aborting headache in a subject, the method comprising orallyadministering to the subject at least once daily at least one dosageform comprising an oily suspension comprising octreotide, wherein theoctreotide in each dosage form is from about 5 mg to about 35 mg (e.g.5, 10, 15, 20, 25, 30 or 35 mg), and wherein the administering occurs atleast 1 hour before a meal or at least 2 hours after a meal, to therebytreat the subject. In particular embodiments of the invention theheadache may be a vascular headache, which may be a migraine or acluster headache or the headache may be caused by IIH.

In a particular embodiment of the invention the oily suspension isformulated into a capsule, and the capsule may be enterically coated. Inparticular embodiments of the invention the oral administration is twicedaily (e.g., administering one or two dosage forms at eachadministration), comprising a first and second administration; thesubject is dosed every 8-16 hours (e.g., every 12 hours); oneadministration takes place at least 6, 8, 10 or 12 hours before a secondadministration; the subject is a human.

In particular embodiments of the invention the first administrationincludes one or two dosage forms and the second administration includesone or two dosage forms. In further embodiments of the invention thefirst administration includes one dosage form and the secondadministration includes one dosage form or the first administrationincludes two dosage forms and the second administration includes onedosage form. or the first administration includes two dosage forms andthe second administration includes two dosage forms.

In further embodiments of the invention one dosage form is administeredtwice a day or two dosage forms are administered twice a day or onedosage form is administered once a day and two dosage forms areadministered once a day.

In particular embodiments of the invention each dosage form comprisesfrom about 19 to about 21 mg of octreotide or each dosage form comprises20 mg of octreotide. In another embodiment of the invention each dosageform comprises from about 27 to about 33 mg of octreotide or each dosageform comprises 30 mg of octreotide

In particular embodiments of the invention the total amount ofoctreotide administered per day is from about 36 to about 44 mg (e.g.,from about 38 to about 42 mg, or 40 mg); or the total amount ofoctreotide administered per day is from about 54 to about 66 mg (e.g.,from about 57 to about 63 mg, or 60 mg); or the total amount ofoctreotide administered per day is from about 72 to about 88 mg (e.g.,from about 76 to about 84 mg, or 80 mg).

If a capsule containing about 30 mg octreotide is administered, then thedose is 30 mg daily or 60 mg daily or 90 mg daily and a maximum of 120mg daily; wherein the administering occurs at least 2 hours after ameal, or at least 1 hour before a meal.

In certain embodiments of the invention each dosage form comprises fromabout 5 to about 35 mg of octreotide and in a particular embodiment ofthe invention each dosage form comprises about 5 or 10 or 15 or 20 or 25or 30 or 35 mg of octreotide.

In particular embodiments of the invention the method occurs over aduration of at least 7 months, for prophylactic treatment and inparticular embodiments of the invention the method can be tapered offafter a few months.

In particular embodiments of the invention the method the method occursover a duration of about a day, or about one to two days or more forabortive treatment. In particular embodiments of the invention thecapsule comprises 20 mg octreotide which is about 3% w/w octreotide. Inother embodiments of the invention the capsule comprises 10 mgoctreotide or 30 mg octreotide.

In particular embodiments of the invention the oily suspension comprisesan admixture of a hydrophobic medium (lipophilic fraction) and a solidform (hydrophilic fraction) wherein the solid form comprises aoctreotide and at least one salt of a medium chain fatty acid, andwherein the medium chain fatty acid salt is present in the compositionat an amount of 10% or more by weight (e.g. at an amount of 11%-16% ormore such as 11%, 12%, 15%, 16% by weight).

In particular embodiments of the invention, upon administration ofoctreotide, the headache is relieved or prophylactically prevented.

Another embodiment of the invention is a method of prophylacticallytreating headache in a subject, the method comprising administering tothe subject at least once daily at least one dosage form comprisingoctreotide, to thereby treat the subject. In particular embodiments ofthe invention the headache is a vascular headache; in furtherembodiments of the invention the vascular headache is a migraine or acluster headache; in a further embodiment of the invention the headacheis caused by IIH; in a further embodiment of the invention theoctreotide is administered orally; in a further embodiment of theinvention the administering occurs at least 2 hours after a meal, or atleast 1 hour before a meal.

Another embodiment of the invention is a method of aborting a headachein a subject, the method comprising orally administering to the subjectat least once daily at least one dosage form comprising octreotide, tothereby treat the subject. In particular embodiments of the inventionthe headache is a vascular headache; in further embodiments of theinvention the vascular headache is a migraine or a cluster headache; ina further embodiment of the invention the headache is caused by IIH; andin a further embodiment of the invention the administering occurs atleast 2 hours after a meal or at least 1 hour before a meal.

The Oily Suspension

The oily suspension as used herein comprises an admixture of ahydrophobic medium (lipophilic fraction) and a solid form (hydrophilicfraction) wherein the solid form comprises a octreotide and at least onesalt of a medium chain fatty acid, and wherein the medium chain fattyacid salt is present in the composition at an amount of 10% or more byweight or 11-20% or 11%, or 12% or 13% or 14% or 15% or 16% or 17%.

In further embodiments of the methods of the invention, the medium chainfatty acid salt in the solid form has a chain length from about 6 toabout 14 carbon atoms; the medium chain fatty acid salt is sodiumhexanoate, sodium heptanoate, sodium octanoate, sodium nonanoate, sodiumdecanoate, sodium undecanoate, sodium dodecanoate, sodium tridecanoateor sodium tetradecanoate, or a corresponding potassium or lithium orammonium salt or a combination thereof; the fatty acid salt is sodiumoctanoate (sodium caprylate); the medium chain fatty acid salt ispresent in the oily suspension at an amount of 11% to 40% by weight, orat an amount of 12% to 18% by weight, preferably 15% by weight. In aspecific embodiment the oily suspension comprises 15% w/w sodiumoctanoate. In another specific embodiment the oily suspension comprises10-20% e.g. 15% w/w sodium decanoate. In another embodiment the solidform in the oily suspension additionally comprises a matrix formingpolymer, which can be for example dextran or polyvinylpyrrolidone (PVP).In another embodiment the polyvinylpyrrolidone is present in the oilysuspension at an amount of about 2% to about 20% by weight, or about 5%to about 15% by weight or about 10% by weight. In a specific embodimentthe polyvinylpyrrolidone is PVP-12 and has a molecular weight of about2500-3000. In another embodiment the hydrophobic medium comprisesglyceryl tricaprylate and in a specific embodiment herein the oilysuspension comprises 50-70% w/w glyceryl tricaprylate. In anotherembodiment the hydrophobic medium comprises a mineral oil, paraffin, afatty acid such as octanoic acid, a monoglyceride, a diglyceride, atriglyceride, an ether or an ester, or a combination thereof. In anotherembodiment the triglyceride is a long chain triglyceride, a medium chaintriglyceride or a short chain triglyceride. In another embodiment thetriglyceride is a short chain triglyceride or a medium chaintriglyceride or a mixture thereof. In another embodiment the short chaintriglyceride is glyceryl tributyrate and the medium chain triglycerideis glyceryl tricaprylate. In another embodiment the hydrophobic mediumfurther comprises an ionic surfactant or a non-ionic surfactant.

In further embodiments the surfactant is a monoglyceride, a cremophore,a polyethylene glycol fatty alcohol ether, a sorbitan fatty acid ester,a polyoxyethylene sorbitan fatty acid ester, Solutol HS15(polyoxyethylene esters of 12-hydroxystearic acid), or a poloxamer or acombination thereof. In further embodiments of the methods of theinvention the monoglyceride is glyceryl monocaprylate, glycerylmonoocatnoate, glyceryl monodecanoate, glyceryl monolaurate, glycerylmonomyristate, glyceryl monopalmitate or glyceryl monooleate or glycerylmonostearate or a combination thereof. In further embodiments of themethod, the polyoxyethylene sorbitan fatty acid ester is polyoxyethylenesorbitan monooleate (also termed polysorbate 80 or Tween 80).

In further embodiments the oily suspension comprises 3% w/wpolyoxyethylene sorbitan monooleate. In further embodiments thehydrophobic medium additionally contains glyceryl monocaprylate and theoily suspension comprises 4% w/w glyceryl monocaprylate. In furtherembodiments the hydrophobic medium consists essentially of glyceryltricaprylate and glyceryl monocaprylate. In further embodiments thehydrophobic medium comprises a triglyceride and a monoglyceride; in someembodiments the monoglyceride has the same fatty acid radical as thetriglyceride; in some embodiments the triglyceride is glyceryltricaprylate and the monoglyceride is glyceryl monocaprylate.

In some embodiments of the method the medium chain fatty acid salt inthe water-soluble composition has the same fatty acid radical as themedium chain monoglyceride or the medium chain triglyceride or acombination thereof. In some embodiments of the method the medium chainfatty acid salt is sodium caprylate (sodium octanoate) and themonoglyceride is glyceryl monocaprylate and the triglyceride is glyceryltricaprylate. In some embodiments of the method the oily suspensioncomprises magnesium chloride.

In one embodiment of the method, the oily suspension comprises about 3%octreotide, 5-15% PVP-12, 10-20% sodium caprylate (sodium octanoate),2-10% surfactants, 50-70% lipid and stabilizer.

In a particular embodiment the formulation consists essentially of anoily suspension which comprises an admixture of a hydrophobic medium anda solid form wherein the solid form comprises a therapeuticallyeffective amount of octreotide and about 10-20% preferably 15% mediumchain fatty acid salt preferably sodium octanoate, and about 5-10%preferably 10% PVP-12; and wherein the hydrophobic medium comprisesabout 20-80%, preferably 30-70% triglyceride preferably glyceryltricaprylate or glyceryl tributyrate or castor oil or a mixture thereof,about 3-10% surfactants, preferably about 6%, preferably glycerylmonocaprylate and Tween 80; in particular embodiments the octreotide ispresent at an amount of less than 33%, or less than 25%, or less than10%, or less than 5% or less than 1%. The solid form may be a particle(e.g., consist essentially of particles, or consists of particles). Theparticle may be produced by lyophilization or by granulation. In aparticular embodiment the solid form may be a particle and may beproduced by lyophilization or by granulation.

In a further embodiment the formulation consists essentially of an oilysuspension which comprises an admixture of a hydrophobic medium and asolid form wherein the solid form comprises a therapeutically effectiveamount of octreotide and about 10-20% preferably 15% medium chain fattyacid salt preferably sodium octanoate and about 5-10% preferably 10%PVP-12; and wherein the hydrophobic medium comprises about 20-80%,preferably 30-70% medium or short chain triglyceride preferably glyceryltricaprylate or glyceryl tributyrate, about 0-50% preferably 0-30%castor oil, about 3-10% surfactants, preferably about 6%, preferablyglyceryl monocaprylate and Tween 80; in particular embodiments theoctreotide is present at an amount of less than 33%, or less than 25%,or less than 10%, or less than 5% or less than 1%.

Oral Dosage Form

In an embodiment, the oral octreotide is administered in a dosage formdescribed herein. An exemplary oral dosage forms includes anenteric-coated oral dosage form comprising a composition comprising asuspension which comprises an admixture of a hydrophobic medium and asolid form wherein the solid form comprises a therapeutically effectiveamount of octreotide, at least one salt of a medium chain fatty acid andpolyvinylpyrrolidone (PVP), wherein the polyvinylpyrrolidone is presentin the composition at an amount of 3% or more by weight (e.g., about 3%to about 20% by weight or about 5% to about 15% by weight), and whereinthe at least one salt of a medium chain fatty acid salt is present inthe composition at an amount of at least 12% or more by weight (e.g.,about 12% to 40% by weight or about 12% to 18% by weight). In anembodiment, the hydrophobic medium comprises glyceryl tricaprylate andthe solid form consists of polyvinylpyrrolidone with a molecular weightof about 3000, and sodium octanoate. In an embodiment, the hydrophobicmedium additionally comprises castor oil or glyceryl monocaprylate or acombination thereof and a surfactant. In an embodiment, the hydrophobicmedium consists of glyceryl tricaprylate, glyceryl monocaprylate, andpolyoxyethylene sorbitan monooleate.

In an embodiment, the solid form consists essentially of octreotide,polyvinylpyrrolidone with a molecular weight of about 3000, and sodiumoctanoate. In an embodiment, the composition comprises about 41% ofglyceryl tricaprylate, about 27% castor oil, about 4% glycerylmonocaprylate, about 2% polyoxyethylene sorbitan monooleate, about 15%sodium octanoate, about 10% polyvinylpyrrolidone with a molecular weightof about 3000, and about 1-3.5% by weight octreotide e.g. 1.5% or 2% or2.5% or 3% or 3.3% octreotide. In an embodiment, the compositioncomprises about 65% glyceryl tricaprylate, about 4% glycerylmonocaprylate, about 2% polyoxyethylene sorbitan monooleate, about 15%sodium octanoate, about 10% polyvinylpyrrolidone with a molecular weightof about 3000 and about 1-5.5% by weight octreotide e.g. 1.5% or 2% or2.5% or 3% or 3.3% or 4% or 5% or 5.5% octreotide. In an embodiment, thecomposition comprises a therapeutically effective amount of octreotide,about 12-21% of sodium octanoate, about 5-10% of polyvinylpyrrolidonewith a molecular weight of about 3000, about 20-80% of glyceryltricaprylate, about 0-50% castor oil, and about 3-10% surfactant. In anembodiment, the composition comprises a therapeutically effective amountof octreotide, about 12-21% of sodium octanoate, about 5-10% ofpolyvinylpyrrolidone with a molecular weight of about 3000, about 20-80%of glyceryl tricaprylate, and about 3-10% surfactant.

In an embodiment, the octreotide is present at an amount of less than33% (e.g., less than 25%, less than 10%, less than 5%, less than 1%). Inan embodiment, the composition comprises about 15% of sodium octanoate,about 10% of polyvinylpyrrolidone with a molecular weight of about 3000,about 30-70% glyceryl tricaprylate and about 6% of surfactant. In anembodiment, the surfactant is glyceryl monocaprylate or polyoxyethylenesorbitan monooleate.

In an embodiment, the solid form comprises a particle or a plurality ofparticles. In an embodiment, the solid form further comprises astabilizer.

In an embodiment, the polyvinylpyrrolidone has a molecular weight ofabout 3000.

In an embodiment, the medium chain fatty acid salt has a chain lengthfrom about 6 to about 14 carbon atoms. In an embodiment, the mediumchain fatty acid salt is sodium hexanoate, sodium heptanoate, sodiumoctanoate, sodium nonanoate, sodium decanoate, sodium undecanoate,sodium dodecanoate, sodium tridecanoate or sodium tetradecanoate, or acorresponding potassium or lithium or ammonium salt or a combinationthereof. In an embodiment, the medium chain fatty acid salt is sodiumoctanoate. In another embodiment, the medium chain fatty acid salt issodium decanoate.

In an embodiment, the hydrophobic oily medium comprises a mineral oil, aparaffin, a fatty acid a monoglyceride, a diglyceride, a triglyceride,an ether or an ester, or a combination thereof. In an embodiment, themedium chain fatty acid salt is a lithium, potassium or ammonium salt.In an embodiment, the hydrophobic oily medium comprises glyceryltricaprylate. In an embodiment, the composition further comprises asurfactant.

The compositions described herein can be administered to a subject i.e.,a human or an animal, in order to treat the subject with apharmacologically or therapeutically effective amount of a therapeuticagent (octreotide) described herein. The animal may be a mammal e.g., amouse, rat, pig, dog horse, cow or sheep. As used herein the terms“pharmacologically effective amount” or “therapeutically effectiveamount” or “effective amount” means that amount of a drug orpharmaceutical agent (the therapeutic agent) that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought by a researcher or clinician and/or halts or reduces theprogress of the condition being treated or which otherwise completely orpartly cures or acts palliatively on the condition, or preventsdevelopment of the condition.

As used herein, the term “treatment” as for example in “method oftreatment” or “treat” or “treating” refers to therapeutic treatment,wherein the object is to reduce or reverse or prevent the symptoms of adisease or disorder. In some embodiments, the compounds or compositionsdisclosed herein are administered prior to onset of the disease ordisorder. In some embodiments, the compounds or compositions disclosedherein are during or subsequent to the onset of the disease or disorder.

The function and advantages of these and other embodiments will be morefully understood from the following example. This example is intended tobe illustrative in nature and is not to be considered as limiting thescope of the systems and methods discussed herein.

EXAMPLE

A novel oral octreotide formulation was tested for efficacy and safetyin a phase III multicenter open-label dose-titration baseline-controlledstudy for acromegaly.

Methods:

155 complete or partially controlled patients were enrolled [IGF-I <1.3upper limit of normal (ULN), and 2-hr integrated growth hormone (GH)<2.5 ng/mL] while receiving injectable somatostatin receptor ligand(SRL) for ≥3 months. Subjects were switched to 40 mg/day oral octreotidecapsules (OOC), dose escalated to 60, and up to 80 mg/day, to controlIGF-I. Subsequent fixed-doses were maintained for 7 month coretreatment, followed by voluntary 6 month extension.

Results:

Of 151 evaluable subjects initiating OOC, 65% maintained response andachieved the primary endpoint of IGF-I <1.3 ULN and mean integrated GH<2.5 ng/mL at the end of the core treatment period and 62% at the end oftreatment (up to 13 months). The effect was durable and 85% of subjectsinitially controlled on OOC, maintained this response up to 13 months.When controlled on OOC, GH levels were reduced compared to baseline andacromegaly-related symptoms improved. Of 102 subjects completing coretreatment, 86% elected to enroll into 6-month extension. 26 subjectsconsidered treatment failures (IGF-I ≥1.3 ULN), terminated early and 23withdrew for adverse events, consistent with those known for octreotideor disease-related.

Conclusions:

OOC, an oral therapeutic peptide achieves efficacy in controlling IGF-Iand GH following switch from injectable SRLs, for up to 13 months, witha safety profile consistent with approved SRLs. OOC appears to beeffective and safe as acromegaly monotherapy.

Oral octreotide capsules (OOC) were employed which facilitate intestinaloctreotide absorption by a novel transient permeability enhancer (TPE)formulation (28). The capsule containing 20 mg non-modified octreotideacetate formulated with TPE enables transient and reversibleparacellular tight junction passage of molecules <70 kDa. The sizelimitation and limited permeability duration ensures that luminalpathogens and endobacterial toxins, are excluded (28). Ingestion of OOCby healthy volunteers achieved circulating octreotide levels andexposure comparable to those observed after subcutaneous octreotideinjection (29).

As a single 20 mg dose of OOC suppressed basal and GHRH-elicited GHlevels in healthy volunteers (29), the drug was tested for efficacy andsafety in a phase III, multicenter, open-label, dose-titrationbaseline-controlled study, in acromegaly. Objectives were to determineOOC effectiveness in maintaining baseline biochemical response for up to13 months, in acromegaly patients in whom prior treatment with aninjectable SRL had been effective i.e. to assess the proportion ofsubjects maintaining baseline response levels following a switch to OOC.

This open-label, maintenance of response, baseline controlled,withdrawal study was conducted to evaluate OOC safety and efficacy inpatients with acromegaly shown to tolerate and respond to injectableSRLs. This IRB-approved multicenter international study continued fromMarch 2012 to November 2013 in 37 sites for ˜15 months and includedscreening, and baseline periods of ˜2 months, core treatment period of≥7 months, voluntary 6-month extension for patients who completed thecore study, and a follow-up period of 2 weeks.

Patient Population

Subjects had confirmed biochemical and clinical evidence for activeacromegaly and were required to receive a stable dose of parenteral SRLsfor at least 3 months prior to screening. At screening, patients had todemonstrate complete or partial response to SRLs, defined as IGF-I<1.3×ULN for age and integrated GH response over 2 hours <2.5 ng/mL.Patients were excluded if they received GH antagonists (within <3months) or dopamine agonists (within <2 months), received radiotherapywithin 10 years, or underwent pituitary surgery within 6 months prior toscreening.

Screening and Baseline Periods

Screening and baseline periods (median 42 days) enabled assessment ofsubject eligibility and for establishing baseline disease control (IGF-1and GH measurements), while receiving parenteral SRL injections. Thefirst OOC dose was administered ≥4-weeks after the last SRL injection.On average, the last SRL dose was given approximately 2 weeks followingScreening visit and 2 weeks prior to Baseline visit.

Treatment Period

The OOC treatment period lasted ≥13 months and comprised a doseescalation (2-5 months) followed by a fixed dose period (8-11 months).The fixed dose period included the time periods up to the completion ofthe core and extension treatment phases (at 7 and 13 monthsrespectively). Enrollment into the extension phase was voluntary. OOCwas administered in the morning and evening (≥1 hour prior to a meal and≥2 hours after a meal).

Dose-Escalation

First OOC dose (20 mg+20 mg) was dispensed ≥4 weeks [mean (SD) 33.3(12.62), median (P25,P75) 31.0 (29.0,35.0) days] after last SRLinjection. OOC dose escalations (to 40+20 mg and if required to 40+40mg), occurred after 2 successive visits if IGF-I was inadequatelycontrolled on a stable dose i.e. >20% increase over prior levels, oremergence of acromegaly symptoms. Visits occurred every 14 days forIGF-I measurements, and results used to guide dosing decisions at thesubsequent visit. Integrated GH levels (measured 2-4 hours following OOCadministration) were measured with every dose escalation. Subjects couldrevert to parenteral SRL therapy at any time, for either safety orefficacy, at the discretion of the site.

Fixed-Dose

Subjects entered into the fixed-dose period when IGF-I levels werenormalized or returned to baseline levels, during ≥2 successive visits.Per protocol, adequately controlled subjects completing the coretreatment period were offered the option to continue a 6-monthextension. At each monthly visit during the core treatment andbi-monthly during the extension, IGF-I was measured and acromegalysymptoms assessed. Integrated GH levels were measured at the beginningand end of the fixed-dose period (core and extension). The optimallyeffective OOC dose achieved during dose escalation was continued for theduration of the fixed-dose period, for up to 13 months.

Endpoints and Statistical Analysis

The primary efficacy endpoint was descriptive and defined as theproportion of responders at the end of the core treatment, with an exact95% CI in the modified intent-to-treat (mITT) population (i.e. allsubjects who had ≥1 post-first-dose efficacy assessment). Response wasdefined, similarly to the inclusion criteria as IGF-I <1.3 ULN for ageand integrated GH <2.5 ng/mL (utilizing Last Observation Carried Forwardimputation (LOCF)). At the end of extension, the primary endpoint wasthe proportion of responders, of all subjects who entered the extension(extension-ITT), and for those who entered the extension as responders,with an exact 95% CI. When continuous measures were reasonablysymmetric, mean values and SD were used, otherwise both mean and medianvalues are presented.

Secondary and exploratory descriptive endpoints included the proportionof subjects who achieved categorical response levels at end oftreatment, based on IGF-I and/or GH levels, and the proportion ofsubjects who maintained response i.e. who remained responders from thebeginning of the fixed-dose to end of the treatment periods.

Acromegaly symptoms (headache, asthenia, perspiration, swelling ofextremities and joint pain), were scored by severity at each visit:absent=0, mild=1, moderate=2, severe=3. The proportion of subjects withimprovement, no change or worsening in overall scores, as well as thosewith 1, 2 or 3 active symptoms from baseline to end of treatment wascalculated.

Assays

IGF-I and GH were measured centrally by IDS-iSYS IGF-I (30) (IS-3900,Immunodiagnostic Systems, Boldon, UK) and IDS-iSYS hGH (31) (IS-3700,Immunodiagnostic Systems) assays, at the Endocrine Laboratory,Universitat Munchen, Germany, and Solstas Lab (Greensboro, N.C., USA).Recombinant standards (98/574 for GH and 02/254 for IGF-I) yieldedinter-assay variability of 4-8.7% (IGF-I) and 1.1-3.4% (GH), andsensitivity 8.8 ng/mL (IGF-I) and 0.04 ng/mL (GH) (30,31). Integrated GHlevels were calculated from the mean of 5 samples collected every 30±5minutes for 2 hours beginning 2 hours following drug dosing (or at timezero at screening and baseline visits) (31). IGF-I measurements wereassayed from a single sample (time zero) and compared to age-relatedreference ranges (30). Routine laboratory safety assessments wereperformed centrally, and all samplings were after ≥8-hour fasting.

During the fixed dose period 46 subjects at a subset of sites underwentpharmacokinetic (PK) evaluation.

Results

Baseline Characteristics

Enrolled subjects had been receiving long-acting SRL injections for 3months to >20 years at all dose ranges. Of the 155 subjects enrolled, 95had IGF-1 ≤1 ULN and GH <2.5 ng/mL at baseline, of whom 67 (43%) had GH<1 ng/mL. 42 subjects entered the study with 1<IGF-1 <1.3 and GH <2.5ng/mL. While eligible patients had to meet criteria of complete orpartial response to injectable SRLs at screening to enter the study,only 88.7% of these subjects were responding to injectable SRLs atbaseline and 17 patients (11%) had IGF-1≥1.3 ULN and/or GH ≥2.5 ng/mL.(See Table 1). 81% of subjects had active acromegaly symptoms despitetreatment on injectables.

TABLE 1 Baseline Characteristics of All Subjects Enrolled [N = 155]Demographics [n (%)] Age Mean (SD) 54.2 (11.54) Gender Female gender 88(56.8) Disease Characteristics [n (%)] Duration of acromegaly <10 years74 (47.7) 10-<20 years 53 (34.2) ≥20 years 28 (18.1) Pituitary tumorcharacteristic Microadenoma 51 (32.9) Intrasellar macroadenoma 53 (34.2)Extrasellar macroadenoma 46 (29.7) Other 5 (3.2) Medical Treatment [n(%)] Previous treatments for acromegaly Surgery 121 (78.1) Medication,other than SRLs 61 (39.4) Radiation 13 (8.4) Surgery followed byradiation 8 (5.2) Radiation followed by surgery 1 (0.6) Previous SRLstreatment [n (%)] Octreotide LAR¹ (mg) 97 (62.6) 10, 20 64 (66% of ptson octreotide) 30, 40, 60 33 (34% of pts on octreotide) Lanreotide² (mg)58 (37.4) 60, 90 27 (47% of pts on lanreotide) 120 31 (53% of pts onlanreotide) Time receiving parenteral SRLs [n (%)] <1 year 21 (13.5)1-<5 years 63 (40.6) 5-<10 years 37 (23.9) >=10 years 34 (21.9) Subjectson Combo 18 (11.6) cabergoline/pegvisomant³ [n (%)] Symptomatic &Biochemical Control Acromegaly symptoms [n (%)] Headache 64 (41.3)Perspiration 65 (41.9) Asthenia 68 (43.9) Swelling of extremities 58(37.4) Joint pain 87 (56.1) At least one symptom 125 (80.6) At least twosymptoms 91 (61.3) At least three symptoms 67 (43.2) IGF-I (ULN) Mean(SD) 0.94 (0.250) Median (P25, P75) 0.89 (0.76, 1.07) GH (mean ng/mL)Mean (SD) 0.93 (0.716) Median (P25, P75) 0.77 (0.44, 1.23) Biochemicalcontrol [n (%)] IGF-I ≤ 1 ULN & 95 (61) GH < 2.5 ng/mL IGF-1 ≤ 1 ULN and67 (43) GH < 1 ng/mL IGF-1 ≤ 1 ULN and 28 (18) 1 ≤ GH < 2.5 ng/mL 1 <IGF-I < 1.3 & 42 (27) GH < 2.5 ng/mL IGF-I ≥ 1.3 and/or 18 (12) GH ≥ 2.5ng/mL ¹Sandostatin LAR, ²Somatuline Autogel ³Subjects on combinationtherapy with cabergoline/pegvisomant within the last 6 months prior toscreening.Subject Disposition

235 patients were screened and most of those failing to meet inclusioncriteria had IGF-I ≥1.3ULN. 155 subjects (67 males, 88 females) wereenrolled, 151 underwent at least one biochemical assessment after firstOOC dose, (mITT), 110 (71%) entered the fixed dose period, 88 elected tocontinue into the 6 months extension and 82 subjects completed 13 monthstreatment.

59 subjects discontinued treatment during the course of the study, most(n=45; 76%), during the dose-escalation period. Early terminations weredue to treatment failure (IGF-I >1.3 ULN; n=26; 16.8%), adverse events(n=23; 14.8%), patient choice (n=7; 4.5%), lost to follow-up (n=2; 1.3%)and sponsor request (n=1; 0.6%).

Efficacy

Overall, 65% of all enrolled subjects (mITT population, N=151, 95% CI58.4-74.2), were responders up to 7 months, and 62% were responders upto 13 months (95% CI 54.9-71.7), as compared to 88.7% at the baselinevisit while on injectable SRLs. Sensitivity analysis (Markov Chain MonteCarlo multiple imputation), showed 65.6% response, consistent withprimary LOCF analysis.

The effect was durable as 85% and 89% of subjects who entered the fixeddose and extension periods respectively as responders, maintainedresponse for up to 13 months treatment. 78.4% [95% CI 68.4, 86.5] ofsubjects who entered the extension were responders at end of treatment(up to 13 months). At the beginning of the fixed dose phase 51/110 (46%)were treated on 40 mg, 25/110 (23%) on 60 mg and 34/110 (31%) on 80 mg.The response up to 13 months, for those patients that entered the fixeddose, was 88% (95% CI 76.1-95.6), 84% (95% CI 63.9-95.5) and 47% (95% CI29.8-64.9), for 40 mg, 60 mg and 80 mg respectively.

Table 2 depicts biochemical response categories at baseline and end oftreatment for all evaluable patients. Integrated GH levels <2.5 ng/mLwere achieved in 93% of mITT subjects at the end of treatment versus 96%at baseline, while GH levels <1 ng/mL were achieved in 78% of subjectsversus 66% at baseline. GH levels were decreased from 0.77 at baselineto 0.48 ng/mL at the end of treatment. While GH was maintained orreduced in 93% of subjects enrolled, 64% achieved IGF-I <1.3×ULN at theend of treatment versus 91% at baseline. 65 subjects (43% of mITT)entered the study with IGF-1≤1 ULN and GH <1 ng/mL, and 49 (32.5%)subjects exhibited this control at end of treatment.

TABLE 2 IGF-I and Mean Integrated GH Suppression at Baseline and End ofTreatment Baseline End of Treatment n (%) n (%) mITT population N = 151N = 151 IGF-I < 1.3 ULN and 134 (88.7) 93 (61.6) GH < 2.5 ng/mL IGF-1 ≤1 ULN and 65 (43.0) 49 (32.5) GH < 1 ng/mL IGF-I ≥ 1.3 ULN 17 (11.3) 58(38.4) AND/OR GH ≥ 2.5 ng/mL IGF-I < 1.3 ULN 138 (91.4) 97 (64.2) IGF-I≤ 1.0 ULN 96 (63.6) 57 (37.7) GH < 2.5 ng/mL 145 (96.0) 140 (92.7) GH <1.0 ng/mL 100 (66.2) 117 (77.5) Median IGF -1 levels 0.90 (0.76-1.07)1.120 (0.870-1.440) (Q1-Q3) Median GH levels 0.77 (0.44-1.23) 0.488(0.244-0.870) (Q1-Q3)

Table 2 shows IGF-I and GH categories at Baseline and end of treatment(core+extension), for all enrolled subjects, with at least one efficacymeasure on post first OOC dose (mITT population). This analysis alsoincludes the 59 subjects who terminated early during the course of thestudy. For this analysis the last concentrations of IGF-I and GH ontreatment were carried forward. mITT, modified Intent to Treat; IGF-1,Insulin Growth Factor-1; GH, Growth Hormone; ULN-Upper Limit of Normal.Q1-Q3, interquartile range

Table 3 depicts biochemical response categories at the beginning of thefixed dose and end of 13 months treatment for those 110 subjectsstabilized on OOC, who entered the fixed dose phase. Of these subjects,91 (83%) were responders at the beginning of the fixed dose phase and 82(75%) were responders at the end of treatment (LOCF imputation). Duringthe fixed dose phase, both GH and IGF1 responses were largelymaintained.

TABLE 3 IGF-I and Mean Integrated GH Suppression at the Beginning ofFixed-dose Period and at the End of 13-Month Treatment. Beginning ofFixed Dose End of Treatment n (%) n (%) Fixed dose population N = 110 N= 110 IGF-I < 1.3 ULN and 91 (82.7) 82 (74.5) GH < 2.5 ng/mL IGF-I ≥ 1.3ULN OR 19 (17.3) 28 (25.5) GH ≥ 2.5 ng/mL IGF-I < 1.3 ULN 91 (82.7) 84(76.4) IGF-I ≤ 1.0 ULN 59 (53.6) 52 (47.3) GH < 2.5 ng/mL 109 (99.1) 105(95.5) GH < 1.0 ng/mL 97 (88.2) 90 (81.8) Median IGF -1 levels 0.98(0.79-1.19) 1.04 (0.83-1.26) (Q1-Q3) Median GH levels 0.40 (0.23-0.66)0.43 (0.23-0.76) (Q1-Q3)

Table 3 shows IGF-I and GH categories at Baseline and end of treatment(core+extension), for all subjects controlled on OOC and entering thefixed dose phase. For this analysis the last on treatment concentrationsof IGF-I and GH were carried forward. IGF-1, Insulin Growth Factor-1;GH, Growth Hormone; ULN, Upper Limit of Normal. Q1-Q3, interquartilerange.

Exploratory analysis showed that the degree of baseline control oninjectable SRLs predicted subsequent response to OOC. The combination ofIGF-I ≤1ULN/GH <2.5 ng/mL and low to mid doses of injectable SRLs(octreotide <30 mg or lanreotide <120 mg), at screening, yielded an OOCresponse rate of 84.5% (49 of 58 subjects).

FIGS. 1A-1D show that mean IGF-I levels were stably maintained betweenthe beginning to the end of the fixed-dose period, up to 13 months inboth the mITT and fixed dose population. The slight increase in meanvalues from baseline towards the end of the dose-escalation period inthe mITT population reflects those subjects failing to be controlled onOOC and discontinuing the study early, all of whom were included in themITT analysis. Median GH levels at Baseline (0.77 ng/mL), wereattenuated within 2 hours of the first OOC dose to 0.40 ng/mL andremained suppressed by the end the extension (0.49 ng/mL). In the fixeddose population median GH levels were 0.77 at baseline, and 0.43 ng/mLat the end of treatment.

80% of subjects entering the fixed dose improved or maintainedacromegaly symptoms (26% maintained, 54% improved). Proportion ofsubjects with at least 1, 2 or 3 acromegaly symptoms decreased from 79%,63% and 45% respectively at baseline to 68%, 48% and 31% at end oftreatment. Acromegaly symptoms improved as demonstrated by the declinefrom baseline (on injectables) to end of treatment (OOC), in theproportion of subjects with active acromegaly symptoms.

Compliance

Over 94% of subjects fully complied with study drug administration inboth the core treatment period and the extension, based on capsulecounts, daily diaries, and a general drug administration and food habitsquestionnaire.

Pharmacokinetics

In 46 subjects studied during the fixed dose phase, mean plasmaoctreotide concentrations increased dose-dependently (see FIG. 2), andmean plasma octreotide trough values (at time zero), were comparable forthe 40 and 60 mg regimens, each of which represent a prior 20 mgovernight dose, with a higher mean trough for the 80 mg regimen, whichrepresents a 40 mg prior overnight dose. Steady-state mean apparentelimination half-life (t½) ranged from 3.19±1.07 (mean±SD, on 40 mg) to4.47±2.02 hrs (on 80 mg)

Safety

Of 155 subjects in the safety population, 138 (89%) experienced an AE.Ninety two percent of events were mild to moderate (see below). Mostcommonly reported organ systems included gastrointestinal, neurologicand musculoskeletal, consistent with the known octreotide safety profile(1,20). Common gastrointestinal AEs (occurring in ≥5%), were nausea,diarrhea, dyspepsia, abdominal pain and distention, flatulence andvomiting, which mostly occurred within the first two months oftreatment, and mostly resolved with treatment continuation (median AEduration=13 days). Common neurologic AEs were headache and dizziness andin the musculoskeletal system, arthralgia and back pain. Infectionsrelated to the gastrointestinal system included a single case of viralgastroenteritis. Hypoglycemia or hyperglycemia were reported in 7 and 11subjects respectively (4.5% and 7%), neither of which led to earlydiscontinuation. Hepatobiliary disorders were reported in 18 (11.6%);with cholelithiasis in 12 (7.7%). Clinically meaningful alterations werenot observed in laboratory safety parameters, vital signs, ECG orphysical examinations. Forty seven percent of AEs occurred within thefirst 3 months of treatment and the incidence significantly decreasedwith time from the dose escalation to the fixed dose phase.

Twenty one subjects (13.5%) experienced 39 serious AEs. Two wereconsidered possibly related to OOC-elevated hepatic transaminases andjaundice occurred in a subject with severe dehydration and a subjectwith suspected bile duct obstruction. Four malignancies were reported,none of which were considered study drug-related. Seriousgastrointestinal infections were not reported.

Twenty-three patients discontinued because of an AE, 19 of which werestudy-drug related, mostly in the first 3 months of treatment; tenearlier terminations were due to gastrointestinal symptoms, includingnausea, diarrhea and abdominal pain. Two deaths were reported, neitherof which were considered OOC-related. (See below). Overall, OOC safetywas consistent with the known octreotide safety profile and acromegalydisease burden, with no new emerging safety signals related to the novelformulation and route of administration.

Discussion

In healthy volunteers 20 mg oral OOA yielded systemic drug exposure(AUC) comparable to 0.1 mg SC dose of octreotide (29). We now showclinical utility and unique mode of action of TPE, whereby a therapeuticpeptide is effectively and safely delivered orally.

OOC is shown to exhibit efficacy in controlling and maintaining IGF-Iand integrated GH levels, for ≥13 months in biochemically controlledacromegaly subjects after switching from injectable SRLs. The primaryefficacy endpoint was achieved by 65% of subjects at the end of the coretreatment and by 62% at the end of 13 months, compared to 89% oninjectable SRLs at baseline. The effect was durable and 85% of 91subjects who entered the fixed-dose period as responders maintained thisresponse for up to 13 months. These results are comparable to thosereported for 41 acromegaly patients responding to injectable octreotideLAR (IGF-1≤1.2 and GH <2.5 ng/mL). 84% of these maintained baselineIGF-UGH control at 6 months (32).

Predictors of the degree of OOC responsiveness included good baselinecontrol on injectable SRLs, (IGF-I ≤1ULN/GH <2.5 ng/mL), and low to middoses of injectable SRLs. OOC also showed efficacy in maintainingclinical response; improved acromegaly symptom severity was noted insubjects who entered the fixed dose phase.

As activity and safety of octreotide are well characterized, the primarygoal was to assess safety and efficacy of an oral octreotideformulation. Parenteral treatment, shown to be effective, was withdrawnand replaced with OOC. As long-term maintenance of response toparenteral octreotide therapy is well established (33) and octreotidetachyphylaxis does not occur in acromegaly, a baseline-control of SRLresponders shown here reflects an appropriate study design. This designalso anticipates clinical practice whereby patients eligible to receiveOOC would be those responding to and tolerating parenteral SRLs and thenswitched to an oral formulation.

The enrolled patient population is representative of acromegaly patientssuitable for OOC therapy. Despite being biochemically controlled byreceiving SRL injections as the standard of care, 81% of subjects stillexhibited persistent acromegaly symptoms at baseline. The duration ofresidual IGF-I suppression after long-acting SRL withdrawal is notknown, but is not expected beyond 8-12 weeks from withdrawal in apatient with active disease (34). In fact, GH levels may revert between4-6 weeks after octreotide LAR withdrawal (35). Accordingly, SRL waswithdrawn 4 weeks prior to the first OOC test dose and clinical andbiochemical response measured for ≥13 subsequent months. Severaladditional factors highlight disease activity of the enrolled subjects.Thirty-nine percent had IGF-I >1 ULN at baseline. Of the patientsenrolled, 41% were being treated with the highest doses of parenteraloctreotide and lanreotide for disease control.

Ninety patients (58%) required >40 mg OOC doses to maintain response.Furthermore, dose up-titration against rising IGF-I levels, as well asthe observed sustained IGF-I normalization achieved with OOC over the13-month duration of the study, allayed the concern of parenteral SRLcarryover effect.

OOC doses selected for dose titration to enable optimal IGF-I controlwere based on PK modeling to achieve effective therapeutic exposure tooctreotide (21,36). Distribution of the fixed dose population by OOCdose requirements were similar to the experience with injectable SRLswhere higher doses are not usually required for adequate control(37,38). PK analyses demonstrated dose proportional exposure to oraloctreotide. Octreotide levels measured prior to the morning dose arereflective of trough levels of the previous night dose, and were withinthe range shown to effectively inhibit GH secretion (21,36).

The results show that under fasting conditions, OOC suppressed GH levelsin nearly all subjects. However, in contrast to GH inhibition, theproportion of subjects maintaining IGF-1 <1.3 ULN was lower. Thissuggests that OOC bioavailability was not a cause of non-response.Hepatic IGF-I generation is log-linear with GH levels (39). Octreotideacts primarily on the pituitary to suppress GH secretion, but alsodirectly inhibits hepatic IGF-I (24,25), and the observed milddiscordant GH and IGF-I responses are commonly observed with SRLinjections. The enhanced response of GH to OOC may also reflect thatfasting GH levels were measured within 2-4 hours following the morningOOC dose, hence may not reflect trough levels. These results underscorethat the somatotroph SSTR2 receptor is a primary target for the oralligand and point to central control of GH hypersecretion by OOC, similarto the primary action of injectables.

The short GH half-life and the pulsatile nature of GH secretion (40,41)confound the accuracy of assessing GH levels based on a single bloodtest. The cutoff value of <2.5 ng/mL (integrated) for GH was chosen todistinguish excess from normal mortality in acromegaly. IGF-I <1.3 ULNwas chosen because of the wide variances of IGF-I values and thechallenge of reproducing a rigorous IGF-I <1 ULN even within individualpatients (30,42).

OOC side effects are largely consistent with underlying acromegaly, aswell as known to be associated with SRLs (16,20) only with no injectionsite reactions. Most adverse events occurred within the first 60 daysand mostly resolved on treatment. Fluctuations in circulating octreotidelevels (e.g. after withdrawal of injectable SRLs and followed by OOCinitiation) are known to result in transient AEs (Sandostatin LARlabel). Gastrointestinal symptoms, associated with octreotide, were alsolargely transient and reported early in the study and resolved oncontinued treatment. Adverse events were not dose-related. Noroute-of-administration-related safety signals or formulation-relatedAEs were encountered.

As OOC exhibits GH/IGF-I control, responders to parenteral SRL injectioncould be switched to OOC and avoid the burden of injections. Althoughcompliance with food restrictions might be perceived as challenging forsome, the advantages of an oral vs parenteral SRL preparation includeconvenience with ease of administration, precluding painful injections,and obviating monthly clinic visits and dependence on health careproviders and/or family members for injection. Moreover, dose titrationand symptomatic control could be achieved more efficiently with an oralSRL than with a 30-day preparation.

This novel TPE technology safely and successfully allowed oral deliveryof a therapeutic peptide that achieved systemic endocrine effects. Twicedaily OOC appears to offer a safe option for acromegaly monotherapy. SeeFIG. 4, which provides a flowchart of the study.

Pharmacokinetic Sampling

During the second monthly visit of the fixed dose phase, and afterreceiving the therapeutic regimen for at least 2 months, 46 subjects ata subset of sites underwent pharmacokinetic (PK) evaluation. Octreotideplasma concentrations were determined at 0 (pre-dose, up to 60 minutesbefore the morning drug administration),), and thereafter at 0.5, 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, and 12 hours post-dosing. Plasmaconcentrations of octreotide were measured using a validated LC/MS/MSmethod by PPD (Richmond, Va.). The limit of quantitation (LOQ) forplasma octreotide concentrations was 0.0227 ng/mL.

Pharmacokinetics Analysis

Actual blood sampling times were used for pharmacokinetic (PK) analysesand per protocol times were used to calculate concentrations forgraphical displays. Values below LLOQ up to the time at which the firstquantifiable concentration or at last time were set to zero. Valuesbelow LLOQ that are embedded between two quantifiable values were set tomissing. PK calculations were done using SAS®. PK parameters werederived from the plasma concentration actual time data, calculated usingnon compartmental analysis. Concentrations that were missing or notreportable were treated as missing values.

PK parameters C₀, C_(max), T_(max), and T_(lag) were taken directly fromthe concentration time data. The elimination rate constant, λz, wascalculated as the negative of the slope of the terminal log-linearsegment of the plasma concentration-time curve. The slope was determinedfrom a linear regression of the natural logarithm of the terminal plasmaconcentrations against time; at least 3 terminal plasma concentrationtime points, beginning with the final concentration ≥LOQ, were selectedfor the determination of λz and the regression had to have a coefficientof determination (r²) ≥0.9000. The range of data used for each subjectwas determined by visual inspection of a semi-logarithmic plot ofconcentration vs. time. Elimination half-life (t½) was calculatedaccording to the following equation:

${t\; 1\text{/}2} = \frac{{0.6}93}{\lambda z}$Area under the curve to the final sample with a concentration ≥LOQ[AUC(0-t)] was calculated using the linear trapezoidal method.SafetyTwo deaths were reported, neither of which were reported as study drugrelated. One was a 37-year-old male with a 10-year history of multiplesurgeries for extrasellar pituitary macroadenoma. Six months after OOCinitiation he had a suspected biliary obstruction, and subsequently alsodeveloped sepsis and multiple organ failure. At autopsy, no evidence forbiliary obstruction was observed. The second was a 60-year-old male withcardiovascular risk factors, diagnosed with pancreatic cancer after sixmonths into the study, and suffered a fatal myocardial infarction.

TABLE 4 Incidence of Most Common (≥5%) Adverse Events by System OrganClass and Preferred Term in all enrolled patients (n = 155), up to 13months treatment. Number of Adverse Event by System Organ Class andPreferred term subjects (%) Gastrointestinal disorders Nausea  46 (29.7)Diarrhea 31 (20)  Abdominal pain upper 15 (9.7) Dyspepsia 14 (9) Abdominal pain 12 (7.7) Flatulence 10 (6.5) Abdominal distension 10(6.5) Vomiting 10 (6.5) Nervous system disorders Headache  56 (36.1)Dizziness  9 (5.8) Musculoskeletal and connective tissue disorderArthralgia  46 (29.7) Back Pain  9 (5.8) General disorders andadministration site conditions Asthenia  38 (24.5) Peripheral edema  26(16.8) Fatigue  8 (5.2) Infections and infestations Nasopharyngitis 12(7.7) Influenza 11 (7.1) Upper respiratory tract infection 11 (7.1) Skinand subcutaneous tissue disorders Hyperhidrosis  36 (23.2) Hepatobiliarydisorders Cholelithiasis 12 (7.7) Vascular disorders Hypertension 11(7.1)

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Having thus described several aspects of at least one embodiment, it isto be appreciated that various alterations, modifications, andimprovements will readily occur to those skilled in the art. Suchalterations, modifications, and improvements are intended to be part ofthis disclosure and are intended to be within the scope of theinvention. Accordingly, the foregoing description and drawings are byway of example only, and the scope of the invention should be determinedfrom proper construction of the appended claims, and their equivalents.

The invention claimed is:
 1. A method of treating acromegaly in asubject, the method comprising: a) orally administering to the subjectat least one dosage form comprising octreotide, wherein the subject isadministered an H2-receptor antagonist or an antacid; b) monitoringIGF-1 and clinical symptoms or biochemical and symptomatic response ofthe subject; and c) if IGF-1 is not normal and clinical symptoms are notcontrolled or biochemical and symptomatic response is not maintained,then increasing the total dose of oral octreotide administered to thesubject.
 2. The method of claim 1, wherein the amount of octreotide ineach dosage form is 20 mg.
 3. The method of claim 1, wherein theadministering of octreotide occurs at least 1 hour before a meal or atleast 2 hours after a meal.
 4. The method of claim 1, wherein the dosageform comprises an oily suspension which is formulated into a capsule. 5.The method of claim 4, wherein the capsule is enterically coated.
 6. Themethod of claim 1, wherein the administering of octreotide occurs twicedaily.
 7. The method of claim 6, wherein the subject is dosed in themorning and in the evening, comprising a first and secondadministration.
 8. The method of claim 7, wherein the firstadministration includes one or two dosage forms and the secondadministration includes one or two dosage forms.
 9. The method of claim7, wherein the first administration includes one dosage form and thesecond administration includes one dosage form.
 10. The method of claim7, wherein the first administration includes two dosage forms and thesecond administration includes one dosage form.
 11. The method of claim7, wherein the first administration includes two dosage forms and thesecond administration includes two dosage forms.
 12. The method of claim1, wherein one dosage form is administered twice a day.
 13. The methodof claim 1, wherein two dosage forms are administered twice a day. 14.The method of claim 1, wherein one dosage form is administered once aday and two dosage forms are administered once a day.
 15. The method ofclaim 1, wherein the total amount of octreotide administered per day tothe subject is 40 mg, 60 mg, or 80 mg.